Osmotic delivery device having a two-way valve and a dynamically self-adjusting flow channel

ABSTRACT

An implantable osmotically driven delivery system having a dynamic, two-way valve and a self-adjusting, variable geometry fluid flow channel. As pressure within the agent delivery system increases, the fluid channel narrows, thereby restricting flow. At exceptionally high pressures, the valve can be designed to close altogether at the orifice or delivery end, or it can provide a minimal leak path so that a maximum fluid flow is never exceeded. At zero or very low pressures, the valve will close completely at the beneficial agent reservoir end, isolating the beneficial agent formulation from external fluid infiltration and thereby eliminating diffusion of external fluid into the beneficial agent formulation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 10/302,104,filed Nov. 21, 2002, now U.S. Pat. No. 7,014,636.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention pertains to osmotically controlled implantabledelivery devices, and more particularly to a delivery device having atwo-way miniature valve and a dynamically self-adjusting flow channelfor the regulation of back-diffusion and fluid delivery rate in anosmotically driven delivery system.

2. Description of the Related Art

Controlled delivery of beneficial agents, such as drugs, in the medicaland the veterinary fields has been accomplished by a variety of methods,including implantable delivery devices, such as implantable osmoticdelivery devices. Osmotic delivery systems are very reliable indelivering a beneficial agent over an extended period of time, called anadministration period. In general, osmotic delivery systems operate byimbibing fluid from an outside environment and releasing controlledamounts of beneficial agent from the delivery system.

Representative examples of various types of delivery devices aredisclosed in U.S. Pat. Nos. 3,987,790; 4,865,845; 5,059,423; 5,112,614;5,137,727; 5,213,809; 5,234,692; 5,234,693; 5,308,348; 5,413,572;5,540,665; 5,728,396; 5,985,305; and 5,221,278, all of which areincorporated herein by reference. All of the above patents generallyinclude some type of capsule having walls, or portions of walls (forexample, semi-permeable membranes) that selectively pass water into theinterior of the capsule. The absorption of water by a water-attractingagent contained within the capsule creates an osmotic pressure withinthe capsule, which then causes a beneficial agent within the capsule tobe expelled. Alternatively, the water-attracting agent may be thebeneficial agent being delivered to the patient. However, in most cases,a separate agent is used specifically for its ability to draw water intothe capsule.

When a separate osmotic agent is used, the osmotic agent may beseparated from the beneficial agent within the capsule by a movabledividing member such as a piston. The structure of the capsule isgenerally rigid such that as the osmotic agent takes in water andexpands, the capsule itself does not expand. As the osmotic agentexpands, the agent causes the movable dividing member to move,discharging the beneficial agent through an orifice or exit passage ofthe capsule. The beneficial agent is discharged through the exit passageat the same volumetric rate that water combines with the osmotic agentthrough the semi-permeable walls of the capsule.

In some known implantable delivery devices, the orifice or exit passageof the capsule is permanently open and thus allows for unimpededdischarge of the beneficial agent. This results in a direct fluidcommunication between the beneficial agent and water in the surroundingtissue of the patient. Thus, back-diffusion of the water into thebeneficial agent reservoir may result. One way in which back-diffusionof water has been reduced is by providing a long orifice or exit passagethat can be a variety of shapes, such as straight or spiral.

In other known implantable delivery devices, the orifice or exit passageof the capsule is covered with a stretchable or elastic member or band,to reduce back-diffusion of water into the beneficial agent reservoir.The stretchable or elastic band allows discharge of the beneficial agentonce a threshold pressure has been overcome. The stretchable or elasticmember or band closes the orifice when the pressure in the device isless than the threshold pressure. However, in these types of devicesthere is little or no control of the pressure that can build up as thedevice adjusts to changes in temperature and/or internal or externalpressure.

In still other known implantable delivery devices, the orifice or exitpassage is at least partially made of a stretchable or elastic materialthat acts to reduce back-diffusion of water into the beneficial agentreservoir. This stretchable or elastic material deforms once a thresholdpressure has been achieved in the device to allow discharge of thebeneficial agent. The stretchable orifice material closes when theinternal pressure in the device is less than the threshold pressure.However, in these types of devices there is little or no control of thepressure that can build up as the device adjusts to changes intemperature and/or internal or external pressure.

In general, osmotic delivery systems rely on the flow of interstitialbody fluid across a rate-limiting membrane (also known as asemi-permeable membrane) to drive the osmotic agent expansion that inturn drives the delivery or discharge of the beneficial agent. Duringthe period immediately following implantation, this interstitial fluidmay also diffuse into the beneficial agent via a beneficial agentdelivery channel (also known as an orifice or exit passage). Suchdiffusion is undesirable because it results in an uncontrolled dilutionof the beneficial agent formulation.

In those prior known designs which attempt to limit or preventback-diffusion without covering the orifice or exit passage, onelimitation has been that a relatively long diffusion path is required toprevent or impede back-diffusion of the fluid into the beneficial agentcompartment. The long orifice, diffusion path, or exit channel in theseknown designs has been formed by molding intricate detail into plasticor by machining high tolerance surfaces into metal. These approaches arecostly to manufacture and occupy a relatively large volume, causing theimplant to have an increased size.

A further drawback of known implantable delivery devices is that thesedevices do not compensate for variations in temperature and internalpressure that can cause the implantable delivery device to deliverbeneficial agent temporarily at high or low rates. Typically, animplantable, osmotically driven delivery system will have been stored atambient room temperature (approximately 20 to 22° C.) prior toimplantation into a patient. Within a few hours following implantation,the system will subsequently come to thermal equilibrium with thepatient (approximately 37° C.). This increase in temperature may causethe beneficial agent formulation within the implantable device toexpand, which may result in a pressurization of the system and a rapid,short-duration delivery of beneficial agent often referred to as astart-up “burst.” This burst is typically followed by a short period ofsomewhat low agent delivery (typically lasting from less than one day to5 days) during which time the osmotic pressure is increased to a degreeequal to that of the piston friction. As the internal pressure of theimplantable device increases, the rate of beneficial agent delivery willrise until it obtains a steady state. Since it is the purpose of anosmotic delivery system to deliver a defined concentration of beneficialagent at a fixed rate, both the start-up “burst” and the subsequent“lag” in delivery are undesirable.

A further aspect of an implantable, osmotically driven beneficial agentdelivery system is that it is subject to external pressure ortemperature changes (e.g., scuba diving, a hot bath, or temperaturecycling during shipping) which may, in turn, result in transient spikesin the beneficial agent delivery profile.

It is possible with the current designs to develop high enough pressureswithin the implantable osmotic delivery device that one or more of theimplant components fails or is expelled. In an effort to reduce thepossibility of component failure or expulsion, previous designs haveprovided grooves in the reservoir walls and/or ribs in thesemi-permeable membrane or holes in the wall of the device which areopen if a component of the device moves out of position. Theseapproaches add cost to the device by requiring additional machining tothe part designs.

Accordingly, it is an objective of the present invention to minimize thestart-up “burst” by containing the beneficial agent with a spring-loadedvalve until the internal, osmotic-induced pressure is great enough toovercome the applied spring force, thereby opening the valve andallowing controlled release of the agent. It is also an objective ofthis invention that the post-start-up “lag” in beneficial agent deliverybe minimized or eliminated as a further result of the elimination of theinitial agent “burst.” A further consequence of this minimization ofstart-up “burst” and post start-up “lag” is that the system may achievethe desired steady-state performance significantly sooner than in knownimplantable agent delivery devices.

Another objective of the present invention is to provide for theelimination of back-diffusion in a relatively inexpensive manner andwithout requiring a relatively large or long orifice, diffusion path, orexit channel.

An additional objective of the present invention is to provide animplantable osmotic delivery device capable of containing the totalosmotic pressure that can develop within the device without requiringrelatively expensive and sophisticated fluid flow bypass pathways.

BRIEF SUMMARY OF THE INVENTION

In accordance with the present invention, an implantable drug deliverysystem for use in mammals (preferably in humans) includes a capsulehaving an impermeable outer layer. The capsule has a beneficial agentdelivery end and a fluid uptake end that are spaced apart from eachother, but not necessarily located on opposite ends of the capsule. Inaddition, the capsule comprises a reservoir containing a beneficialagent; a movable dividing member separating the reservoir from theosmotic engine; and an osmotic engine. The delivery system includes ameans for controlling beneficial agent flow through the beneficial agentdelivery end that substantially prevents flow of beneficial agent out ofthe capsule when pressure within the capsule is above an upperpredetermined pressure and prevents flow of fluid into the capsulethrough the beneficial agent delivery end when the pressure within thecapsule is below a lower predetermined pressure. However, beneficialagent is substantially allowed to flow out of the capsule through thebeneficial agent delivery end when the pressure within the capsule isbetween the lower and upper predetermined pressures.

In accordance with another aspect of the present invention, a device fordynamically regulating the flow of a beneficial agent from a pressurizedbeneficial agent delivery system includes a hollow body having a lowerport and an upper port. The device also includes a means for controllingflow of interstitial fluid through the hollow body when pressure by thebeneficial agent acting upon the means for controlling flow is below alower predetermined pressure. The device also includes a means forcontrolling beneficial agent flow out of the device when the pressure inthe device is above an upper predetermined pressure. The beneficialagent is substantially allowed to flow out of the device when thepressure in the device is between the lower and upper predeterminedpressures.

According to a further aspect of the invention, a method of variablycontrolling the delivery of a beneficial agent from an implantable drugdelivery system includes the steps of providing a capsule having abeneficial agent delivery end and a fluid uptake end, an agent reservoircontaining a beneficial agent, an uptake reservoir containing a fluidattracting agent, and a movable dividing member between the agentreservoir and the uptake reservoir. The beneficial agent reservoir andthe uptake reservoir are positioned adjacent the beneficial agentdelivery end and the fluid uptake end, respectively. The method alsoincludes the step of substantially preventing the flow of fluid into thecapsule when a pressure within the capsule is below a lowerpredetermined pressure and flow of beneficial agent out of the capsulewhen a pressure within the capsule is above an upper predeterminedpressure. The method still further includes the step of variablycontrolling the flow of the beneficial agent out of the capsule when thepressure is between the lower and upper predetermined pressures.

In accordance with yet another aspect of the invention, a method ofvariably controlling the delivery of a beneficial agent from animplantable osmotically driven delivery system includes the steps ofdisplacing a movable closing member of a valve assembly with respect toa lower port via application of fluid pressure thereon from a beneficialagent reservoir to thereby create an opening between the closing memberand the lower port. The method also includes the steps of increasing thesize of the opening via increased pressure from the beneficial agentreservoir and allowing a beneficial agent from the beneficial agentreservoir to pass through the lower port and through the valve assembly.The method further includes the step of variably controlling thebeneficial agent flow through the valve assembly such that thebeneficial agent flow is directly proportional to the pressure appliedby the beneficial agent against the movable closing member until thepressure approaches a predetermined maximum pressure, at which time thebeneficial agent flow becomes more restricted as the pressure increases.

The present invention substantially prevents back-diffusion during thestart-up phase by causing the spring-loaded valve to be closed duringthis time, effectively preventing fluid communication between thebeneficial agent and interstitial fluids until the system issufficiently pressurized, with the beneficial agent pumping at asufficient rate, to disallow diffusion by the body fluid into thebeneficial agent reservoir.

The present invention also provides the advantage of eliminating theneed for a relatively long orifice, diffusion path or exit channel toprevent back-diffusion in an implantable osmotically driven deliverydevice.

In addition, the present invention provides an implantable osmoticallydriven delivery device which has the capability to withstand and containthe full system osmotic pressure, an especially critical considerationwith any highly potent beneficial agent, without requiring relativelyexpensive and sophisticated fluid flow bypass pathways.

Furthermore, the present invention eliminates the need for and cost of aseparate fluid bypass pathway.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The invention will be described in greater detail with reference to theaccompanying drawings in which like elements bear like referencenumerals, and wherein:

FIG. 1 is a cross-sectional side view of an osmotic agent deliverydevice including a two-way valve and a dynamically self-adjusting flowchannel in a normal condition;

FIG. 2 a is a cross-sectional side view of an upper section of anosmotic agent delivery device including a two-way valve and adynamically self-adjusting flow channel, in which the closing member hasbeen axially displaced;

FIG. 2 b is a cut away view of the valve shown in FIG. 2 a, showing theelongated cylindrical stem.

FIG. 3 is a cross-sectional side view of an upper section of an osmoticagent delivery device including a two-way valve and a dynamicallyself-adjusting flow channel, in which the closing member has beenaxially displaced to a greater extent than that shown in FIGS. 2 a and 2b;

FIG. 4 is a cross-sectional side view of an upper section of an osmoticagent delivery device including a two-way valve and a dynamicallyself-adjusting flow channel, in which an upper chamber thereof issubstantially closed off; and

FIG. 5 is a cross-sectional side view of a two-way valve and adynamically self-adjusting flow channel, according to a secondembodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pressure activated, two-way valve andself-adjusting flow channel for use in regulating fluid flow in animplantable osmotically driven beneficial agent delivery system. Thecomponents of the two-way valve and self-adjusting flow channel aredesigned to substantially prevent the passage of interstitial fluidtherethrough when the pressure within a beneficial agent reservoir isbelow a lower predetermined pressure and prevent passage of beneficialagent therethrough when the pressure within a beneficial agent reservoiris above an upper predetermined pressure. This is accomplished by thenarrowing of the fluid flow channel when the pressure within thebeneficial agent reservoir is either below a lower predeterminedpressure or above a higher predetermined pressure. At exceptionally highpressure, the valve can be designed to close altogether at the orificeend, or it can provide a minimal leak path so that a maximum fluid flowis never exceeded. At zero or very low pressures, the valve will closecompletely or provide a minimal leak path at the beneficial agentreservoir end, thereby substantially isolating the agent formulationfrom external fluid infiltration and eliminating diffusion of externalfluid into the beneficial agent formulation. While these performancecriteria can be achieved with various discrete components (e.g., reliefvalve, flow restrictor, check valve), this invention combines all thedesired performance with a single, simple, and low cost mechanism.

While it is impractical to expect that external effects, such asexternal pressure or temperature changes, on the delivery system may beregulated or eliminated, the present invention minimizes the errorcontribution of them by requiring a significant increase in the overallpressure at which the system still dispenses beneficial agent. Byforcing the system to pump or deliver beneficial agent at higherpressures, there is a reduction in overall variability of the pumping ordelivery rate. As an example, a 0.01 psi (pounds per square inch)pressure increase will contribute substantially more error to a systemdispensing at a nominal pressure of 0.10 psi than a 0.10 psi increasewill to a system dispensing at 3 psi (10% vs. 3%).

FIG. 1 illustrates an implantable osmotically driven beneficial agentdelivery system 1 having a capsule 2. The capsule 2 has an impermeableouter layer and includes a beneficial agent reservoir 50 and an osmoticagent reservoir 52. The beneficial agent delivery system 1 alsopreferably includes a movable piston 54 positioned between thebeneficial agent reservoir 50 and the osmotic agent reservoir 52. Afluid permeable membrane 56 is provided at the fluid uptake end 16 ofthe beneficial agent delivery system 1. The fluid permeable membrane 56can be any suitable membrane or combination of membranes in a shape thatcan adequately control the amount of fluid entering into the capsule 2.Additionally, the membrane 56 should also be selected to prevent thecompositions within the capsule 2 from passing out of the capsule. Avalve assembly 10 is provided at the beneficial agent delivery end 14 ofthe capsule 2.

The capsule 2 must be sufficiently strong to ensure that it will notleak, crack, break, or distort so as to expel its beneficial agentcontents under stresses it would be subjected to during use while beingimpermeable. In particular, it should be designed to withstand themaximum osmotic pressure that could be generated by the water-swellableosmotic agent in reservoir 52. Capsule 2 must also be chemically inertand biocompatible, that is, it must be non-reactive with the beneficialagent formulation as well as the body. Suitable materials generallycomprise a non-reactive polymer or a biocompatible metal or alloy. Thepolymers include acrylonitrile polymers such asacrylonitrile-butadiene-styrene terpolymer, and the like; halogenatedpolymers such as polytetrafluoroethylene, polychlorotrifluoroethylenecopolymer tetrafluoroethylene and hexafluoropropylene polyimide;polysulfone; polycarbonate polyethylene; polypropylene;polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and thelike. The water vapor transmission rate through compositions useful forforming the reservoir are reported in J. Pharm. Sci., Vol. 29, pp.1634-37 (1970); Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1953);Materials Engineering, Vol. 5, pp. 38-45 (1972); Ann. Book of ASTMStds., Vol. 8.02, pp. 208-211 and pp. 584-587 (1984); and Ind. and Eng.Chem., Vol. 49, pp. 1933-1936 (1957). The polymers are known in TheHandbook of Common Polymers by Scott and Roff, CRC Press, ClevelandRubber Co., Cleveland, Ohio. Metallic materials useful in the inventioninclude stainless steel, titanium, platinum, tantalum, gold and theiralloys as well as gold-plated ferrous alloys, platinum-plated ferrousalloys, cobalt-chromium alloys and titanium nitride coated stainlesssteel. A reservoir made from titanium or a titanium alloy having greaterthan 60%, often greater than 85%, titanium is particularly preferred formost size-critical applications.

The osmotic agent reservoir 52 may contain any suitable osmotic agent,examples of which include, but are not limited to, a non-volatile watersoluble osmagent, an osmopolymer which swells on contact with water, ora mixture of the two. Representative osmagents or osmopolymers aredescribed, for example, in U.S. Pat. Nos. 5,413,572 and 6,270,787, whichare hereby incorporated herein by reference. Osmotic agents, such assodium chloride with appropriate lubricants, binders, and viscositymodifying agents, such as sodium carboxymethylcellulose or sodiumpolyacrylate can be prepared in various forms. Sodium chloride in tabletform is a preferred water swellable agent as described, for example, inU.S. Pat. No. 5,728,396, which is hereby incorporated herein byreference. The osmotic agent should be capable of generating between 0and 5200 psi.

Materials for the fluid permeable membrane 56 are those that aresemipermeable and that can conform to the shape of the reservoir uponwetting and make a water tight seal with the rigid surface of thereservoir. The semipermeable membrane expands as it hydrates when placedin a fluid environment so that a seal is generated between the matingsurfaces of the membrane and the reservoir. The polymeric materials fromwhich the membrane may be made vary based on the pumping rates anddevice configuration requirements and include, but are not limited to,plasticized cellulosic materials, enhanced polymethylmethacrylate suchas hydroxyethylmethacrylate (HEMA) and elastomeric materials such aspolyurethanes and polyamides, polyether-polyamide copolymers,thermoplastic copolyesters and the like. Further semipermeablecompositions are described in U.S. Pat. Nos. 5,413,572 and 6,270,787,which are hereby incorporated herein by reference.

The movable dividing member can be of any shape that isolates thewater-swellable agent from the beneficial agent formulation, including,but not limited to, a sheet or a piston 54. The movable dividing memberisolates the water-swellable agent in reservoir 52 from the beneficialagent formulation in reservoir 50 and must be capable of sealably movingunder pressure within capsule 2. The movable piston 54 is preferablymade of a material that is of lower durometer than the capsule 2 andthat will deform to fit the interior of the capsule 2 to provide afluid-tight compression seal with the capsule 2. The materials fromwhich the movable dividing member or piston is made are preferablyelastomeric materials that are impermeable and include, but are notlimited to, polypropylene, rubbers such as EPDM, silicone rubber, butylrubber, and the like, fluoro elastomers, perfluoro elastomers, andthermoplastic elastomers such as plasticized polyvinylchloride,polyurethanes, Santoprene®, C-Flex® TPE, astyrene-ethylene-butylene-styrene copolymer (Consolidated PolymerTechnologies Inc.) and the like. The movable dividing member, or movablepiston, may be of a compression-loaded design.

Implantable drug delivery devices of this invention are useful todeliver a wide variety of active agents. These agents include, but arenot limited to, pharmacologically active peptides and proteins, genesand gene products, other gene therapy agents, and other small molecules.The polypeptides may include, but are not limited to, growth hormone,somatotropin analogues, somatomedin-C, Gonadotropic releasing hormone,follicle stimulating hormone, luteinizing hormone, LHRH, LHRH analoguessuch as leuprolide, nafarelin and goserelin, LHRH agonists andantagonists, growth hormone releasing factor, calcitonin, colchicine,gonadotropins such as chorionic gonadotropin, oxtocin, octreotide,somatotropin plus an amino acid, vasopressin, adrenocorticotrophichormone, epidermal growth factor, prolactin, somatostatin, somatotropinplus a protein, cosyntropin, lypressin, polypeptides such as thyrotropinreleasing hormone, thyroid stimulation hormone, secretin, pancreozymin,enkephalin, glucagons, endocrine agents secreted internally anddistributed by way of the bloodstream, and the like. Further agents thatmay be delivered include α₁ antitrypsin, factor VIII, factor IX andother coagulation factors, insulin and other peptide hormones, adrenalcortical stimulating hormone, thyroid stimulating hormone and otherpituitary hormones, interferon including, but not limited to, α,β, andδ, erythropoietin, growth factors such GCSF, GMCSF, insulin-like growthfactor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1receptor antagonist, tumor necrosis factor, pancreatic enzymes, lactase,cytokines, interleukin 2, tumor necrosis factor receptor, tumorsuppresser proteins, cytotoxic proteins, and recombinant antibodies andantibody fragments, and the like.

The above agents are useful for the treatment of a variety of conditionsincluding, but not limited to, hemophilia and other blood disorders,growth disorders, diabetes, leukemia, hepatitis, renal failure, HIVinfection, hereditary diseases such as cerebroside deficiency andadenosine deaminase deficiency, hypertension, septic shock, autoimmunediseases such as multiple sclerosis, Graves disease, systemic lupuserythematosus and rheumatoid arthritis, shock and wasting disorders,cystic fibrosis, lactose intolerance, Crohn's disease, inflammatorybowel disease, and gastrointestinal and other cancers.

The active agents may be anhydrous or aqueous solutions, suspensions orcomplexes with pharmaceutically acceptable vehicles or carriers suchthat a flowable formulation is produced that may be stored for longperiods on the shelf or under refrigeration, as well as stored in animplanted delivery system. The formulations may include pharmaceuticallyacceptable carriers and additional inert ingredients. The active agentsmay be in various forms, such as uncharged molecules, components ofmolecular complexes or pharmacologically acceptable salts. Also, simplederivatives of the agents (such as prodrugs, ethers, esters, amides,etc.) which are easily hydrolyzed by body pH, enzymes, etc., can beemployed.

Referring now to FIGS. 2 a and 2 b, valve body halves 30 and 32 arepreferably made of titanium, steel, and their alloys, thermoplasticsincluding polyether ketone (PEEK) or liquid crystal polymers (LCP) andthe like. More preferably valve body halves 30 and 32 are made of aliquid crystal polymer.

Spring 24 is preferably made of spring steels including stainless steelor beryllium/copper or injection molded polymer or plastic. The springmaterial should provide dimensionality while having a wire thicknessthat can be manufactured and inserted into the valve. More preferablyspring 24 is made of stainless steel for a fine wire spring or asuitable plastic for a thicker wire spring. The profile of spring 24 maybe round, square, or any other appropriate shape. Spring 24 provides thefluid path from reservoir 50 through upper port 22.

Stem 46 and guide post 48 may be made of the same materials as valvebody halves 30 and 32, or elastomeric materials such as fluoroelastomers, perfluoro elastomers, thermoplastic elastomers such asC-Flex® or Santoprene®, hard plastics, or the like. Stem 46 and guidepost 48 are preferably made of thermoplastic elastomers, perfluoroelastomers, or hard plastic.

In operation, fluid from the exterior of the capsule 2 passes throughthe membrane 56 and into the capsule 2. Some of the fluid is thenabsorbed by the osmotic agent in reservoir 52, thereby causing theosmotic agent to swell. As the osmotic agent swells, the increasedvolume thereof causes the movable piston 54 to push the beneficial agenthoused in the beneficial agent reservoir 50 to be dispensed through thevalve assembly 10 and into the patient's body (FIG. 1). However, thebeneficial agent is only dispensed through the valve assembly 10 whenthe pressure within the capsule 2 is greater than a lower predeterminedpressure. The mechanics of the valve assembly 10 will be described ingreater detail below with reference to FIGS. 1-5.

As can be seen in FIGS. 1, 2 a and 2 b, the valve assembly 10 includes avalve body 12 containing a plurality of interconnected fluid chambers 60and 70. The valve assembly 10 should have a height measurement largerthan the diameter measurement. In other words, the ratio of the heightto width of the valve assembly should be greater than 1:1. The height towidth ratio of the valve assembly should be less than 1:5. Preferablythe height to width ratio of the valve assembly is between 1:1 and 1:2.The valve assembly preferably has a diameter of about 1 to about 10 mm,more preferably about 3 to about 6 mm. The valve assembly preferably hasa height of about 5 to about 10 mm.

The valve body 12 preferably includes two identical halves 30 and 32.The valve assembly 10 further includes a lower port 20 and an upper port22. A lower fluid chamber 60 is positioned adjacent to and in fluidcommunication with the lower port 20. An upper fluid chamber 70 ispositioned between and in fluid communication with the upper port 22 andthe lower fluid chamber 60.

The lower fluid chamber 60 includes a first surface 62 having a conicalfrustum shape and a second surface 64 having a cylindrical shape. Thediameter of the lowermost portion of the first surface 62 is smallerthan the diameter of the lower port 20. The diameter of the uppermostportion of the first surface 62 is substantially the same as thediameter of the second surface 64. The lower fluid chamber 60 alsoincludes a third surface 66 that is substantially perpendicular to thesecond surface 64.

A passageway 74, formed at the intersection of the third surface 66 andthe upper fluid chamber 70, is provided between the upper and lowerfluid chambers 70, 60. The diameter of the upper port 22 issubstantially smaller than the diameter of the upper fluid chamber 70and a top surface 72 (also substantially perpendicular to second surface64) is provided therebetween.

As illustrated in FIGS. 2 a and 2 b, the valve assembly 10 contains amovable closing member 40 having a cylindrical seal 44 and a conicalfrustum 42 attached to an elongated cylindrical stem 46 (shown moreclearly in FIG. 2 b ) and a guide post 48. Stem 46 is slightly smallerin diameter than spring 24. Guide post 48 should have a diameterslightly smaller than the diameter of upper port 22. The movable closingmember 40 also includes a substantially flat upper surface 90. Theclosing member 40 and the cylindrical stem 46 may be fabricated as asingle piece, preferably by molding, or they may be separatelyfabricated and attached in any known manner. Additionally, the stem 46may be fabricated with a threaded end that is configured to mate with athreaded opening provided on the upper surface 90 of the closing member40.

The movable closing member 40 can be moved from a lowermost positionsubstantially adjacent the first surface 62 to an uppermost positionsubstantially adjacent the third surface 66. The conical frustum 42 ofthe closing member 40 is shaped to substantially mate with the firstsurface 62 when the closing member 40 is in the lowermost position.Additionally, the upper surface 90 of the closing member 40 is alsoshaped to substantially cover the third surface 66 of the lower fluidchamber 60 when the closing member is in the uppermost position. Whenthe movable closing member 40 is in either of the above describedpositions, the flow of beneficial agent from the beneficial agentreservoir 50 through the valve assembly 12 is substantially impeded.

A spring 24 is provided around the cylindrical stem 46 and between thetop surface 72 and the upper surface 90. The spring 24 is preferably ahelical compression spring and is shown as such in FIG. 1. However, itis to be understood that any other suitable spring may be used in placeof the helical compression spring.

At zero or low pressures (0.5 to 10 psi, for example), such as can beexpected during storage or initial pump startup, the spring 24 maintainsthe closing member 40 in a position to substantially prohibit fluid flowin either direction of the valve assembly 10. Cylindrical seal 44prevents fluid flow across the lower port 20 such that there issubstantially no fluid communication between any beneficial agentcontained within the beneficial agent reservoir 50 and, once implanted,interstitial fluid present at the upper port 22. Further, as can be seenin FIG. 2, movable closing member 40 is designed to travel through somepredetermined axial displacement while still maintaining a seal at lowerport 20. This occurs because the cylindrical seal 44 has a height thatis greater than the height of the lower port 20. This feature allows thevalve assembly 10 to contain the increased agent formulation volume thatresults from thermal expansion upon implantation without the startupburst that occurs in many devices.

The pressure necessary to either keep valve assembly 10 in the closedposition (as illustrated in FIGS. 2 and 4) or in an open position (asillustrated in FIG. 3) is dependent, for example, on the viscosity ofthe beneficial agent formulation; the desired rate at which thebeneficial agent formulation is delivered from the system; the springconstant of spring 24; and/or the amount of room spring 24 takes up invalve assembly 10.

The psi (pounds per square inch) range from low to high pressure (fromvalve open to valve closed) needs to be very narrow, but could beanywhere in the range of about 0.1 to about 2000 psi. Preferably therange is about 0.5 to about 100 psi.

The valve assembly 10 is fabricated by positioning the helicalcompression spring 24 over the cylindrical stem 46 of the movableclosing member 40. The assembly 10 is subsequently captured between thetwo valve body halves 30 and 32 with the conical frustum 42 andcylindrical seal 44 oriented to engage the first surface 62 of lowerfluid chamber 60 and the lower port 20, respectively. The resultingassembly will cause the spring 24 to be under a compressive load,forcing the conical frustum 42 to seal against the first surface 62 atlower fluid chamber 60. Consequently, the valve assembly 10 is normallyclosed to fluid flow at the lower port 20. The body halves 30 and 32 canbe sealed together in any of a number of ways known in the art. Forexample, using adhesives, ultrasonic welding, or mechanical mating.

FIG. 3 illustrates the valve operation once the fluid pressure at thelower port 20 exceeds the minimal value (for example, about 5 psi) aswould be the case for normal operation. In this case, the movableclosing member 40 will be displaced axially upward toward the upper port22, creating an opening at the lower port 20 and allowing the beneficialagent from the beneficial agent reservoir 50 to be pumped through thelower port 20 then through, successively, fluid chambers 60 and 70, andfinally exiting upper port 22. The cross-sectional area of the opening,and thus the fluid flow, is directly proportional to the pressureapplied by the fluid against the movable closing member 40 until suchtime as the pressure begins to approach some predetermined maximumvalue. In this case, the valve action is reversed as the upper surface90 of the closing member 40 approaches the third surface 66 of the lowerfluid chamber 60.

The spring 24 defines a spiral fluid flow path through the upper fluidchamber 70. The spring 24 compresses as the movable closing member 40 isforced upward by the flowing agent. Consequently, as the fluid pressureinside the beneficial agent reservoir 50 and the chamber 60 increases,the lower port 20 opens more fully while the fluid flow pathprogressively narrows, thus becoming more restrictive. Normal flow willcause a balance between the opposing forces of the spring and the fluidpressure while low fluid flow will typically be completely impeded bythe compression spring 24 causing lower port 20 to be closed by themovable closing member 40. On the other hand, high fluid flow willtypically be substantially impeded by the upper surface 90 of themovable closing member 40 substantially closing off the passageway 74.Compression of spring 24 reduces the flow path between lower fluidchamber 60 and upper port 22.

FIG. 4 shows the valve condition when a maximum pressure is reached (forexample, about 20 psi). The movable closing member 40 has been driven inFIG. 4 to its uppermost position, forcing the movable member againstthird surface 66 of lower fluid chamber 60. This both limits the travelof the movable closing member 40 and either closes fluid communicationbetween lower fluid chamber 60 and upper fluid chamber 70, or, in thepreferred embodiment, limits the fluid flow around the movable closingmember 40 to some predetermined minimal amount via a small fluid bypasschannel around movable closing member 40. As the pressure is relieved,the fluid path increases in cross-sectional area at the third surface66, thereby again allowing increased fluid flow. In this manner, fluidflow is continuously regulated to compensate for pressure andtemperature variations, which would otherwise cause sub-optimalperformance.

The above detailed description refers to a particular embodiment of thepresent invention. However, it should be obvious from the abovedisclosure that a broad range of materials, fabrication technologies,and alternative embodiments can be readily achieved. One furtherembodiment of this invention includes a separate small fluid bypasschannel that can be formed by either a small hole through movableclosing member 40 or a notch formed in one edge of movable closingmember 40.

As an example, FIG. 5 illustrates another preferred embodiment of thepresent invention, in which a valve assembly 80 can be fabricated as asilicon microstructure or molded in thermoplastic. As seen in FIG. 5,the valve assembly 80 includes a single chambered valve body 81 havingan integrally formed cantilever spring arm 82 in place of thecompression spring described hereinabove. The cantilever spring arm 82may be made of metal (such as those described above for valve bodyhalves 30 and 32) or a thermoplastic. Additionally, the movable closingmember 86 is in the form of a spheroid and is attached to the free endof the cantilever spring arm 82. The movable closing member 86 may bemade of a metal or metal alloy (such as those described above for valvebody halves 30 and 32), a thermoplastic, or an elastomer. The upper andlower ports of this embodiment do not have to have the same diameter, aslong as movable closing member 86 closes off the vertical portion of theupper or lower port when pressure is either lower or higher than apredetermined pressure. However, other shapes may also be used for theclosing member 86. One potential benefit is that this embodimentpresents an integral structure rather than an assembly and discretecomponents. Still another benefit is its extremely small overall size.

Furthermore, while the above description has described application to anosmotically driven agent delivery system in particular, it should beobvious that the present invention may be applied to any pressurizedfluid delivery system.

The above-described exemplary embodiments are intended to beillustrative in all respect, rather than restrictive, of the presentinvention. Thus, the present invention is capable of many variations anddetailed implementation that can be derived from the descriptioncontained herein by a person skilled in the art. All such variations andmodifications are considered to be within the scope and the spirit ofthe present invention as defined by the following claims.

1. A device for dynamically regulating flow of a fluid from apressurized fluid delivery system, the device comprising: a hollow bodyhaving a lower port and an upper port, wherein the hollow body comprisesa closing member and a spring provided within the hollow body, whereinthe spring comprises a cantilevered spring arm having two ends, one ofthe ends being attached to an inner surface of the hollow body, andfurther maintains the closing member in a position to substantiallycover one of the lower and upper ports when the pressure acting upon thedevice by the fluid is below the lower predetermined pressure or abovethe upper predetermined pressure; wherein the closing member comprises aspherical member connected to the other end of the spring arm; and meansfor controlling fluid flow through the hollow body, the controllingmeans substantially preventing fluid flow when pressure acting upon thedevice by the fluid is below a lower predetermined pressure and when thepressure is above an upper predetermined pressure, and substantiallyallowing fluid flow when the pressure is between the lower and upperpredetermined pressures.
 2. The device according to claim 1, wherein theclosing member includes an upper section, a middle section, and a lowersection; the upper section having a cylindrical shape; the middlesection having a conical frustum shape; and the lower section having acylindrical shape which is smaller in diameter than the diameter of theupper section.
 3. The device according to claim 1, wherein the hollowbody comprises: an upper fluid chamber and a lower fluid chamber; thelower port being positioned adjacent the lower fluid chamber; and theupper port being positioned adjacent the upper fluid chamber.
 4. Thedevice according to claim 3, wherein the lower fluid chamber has a lowerportion and an upper portion; the lower portion having a conical frustumshape and the upper portion having a cylindrical shape; the upper fluidchamber having a cylindrical shape, wherein the diameter of the upperportion of the lower fluid chamber is larger than the diameter of theupper fluid chamber; the lower fluid chamber having a substantially flatupper surface formed between the upper portion of the lower fluidchamber and the upper fluid chamber; wherein the closing member ishoused within the lower fluid chamber; the middle section of the closingmember being configured to matingly fit with the lower portion of thelower fluid chamber and the lower section of the closing member beingconfigured to matingly fit within and substantially seal the lower port;and wherein the closing member has a substantially flat top surfacehaving a diameter that is smaller than the diameter of the upper portionof the lower fluid chamber and larger than the diameter of the upperfluid chamber, such that the top surface of the closing member iscapable of substantially blocking off fluid communication between theupper and lower fluid chambers when the closing member is in abuttingrelationship with the upper surface of the lower fluid chamber.
 5. Thedevice according to claim 3, wherein the spring comprises a compressionspring and is positioned against a wall located between the upper portand the upper fluid chamber and applies force against the closing memberto maintain the closing member against a lower section of the lowerfluid chamber when the pressure is below the lower predeterminedpressure.
 6. The device according to claim 3, wherein when the pressureis above the upper predetermined pressure, the closing membersubstantially closes off fluid communication between the upper port andthe lower fluid chamber.
 7. The device according to claim 3, whereinwhen the pressure is between the lower and upper predeterminedpressures, the closing member is maintained in a position substantiallybetween the lower and upper ports.
 8. The device according to claim 1,wherein the hollow body comprises a silicon microstructure.